A correlation between chronic morphine use and immunosuppression has been well established in the recent past. However, the detailed mechanisms by which morphine affects the immune system is not yet characterized. Recent studies have shown that morphine treatment affects all the three major components of the immune system; T-lymphocytes, B-lymphocytes and macrophages. The effects ranged from changes in the weight of primary lymphoid organs, alterations in the ratio of T-cell subpopulations and responsiveness to cytokines. Since, T-lymphocytes play a central role in immune response and modulate the function of other immunocompetent cells, it is important to investigate the mechanism of morphine action on T-cells. The activation of thymocytes/T-cells is regulated by the coordinate production of cytokines and expression of cytokine receptors. The major focus of this project is to determine the mechanisms by which morphine inhibits IL-1 induced thymocyte and T-lymphocytes proliferation. This proposal is based on the hypothesis that chronic morphine treatment blocks the proliferative signaling pathways in thymocytes and T-lymphocytes by either 1) inhibiting the expression of cytokine genes or 2) by down regulating cytokine receptors or 30 by inhibiting signal transduction pathway of cytokine receptors. Investigations will be carried out to determine the direct and indirect mechanism by which morphine inhibits IL-2 synthesis in thymocytes and T-lymphocytes. Transcriptional regulation of IL-2 synthesis and IL-2 receptor mediated signal transduction will be investigated. These studies would help to understand the relationship between morphine induced immunosuppression and the prevalence of HIV infection in the drug abuse population. Since morphine is currently administered chronically to patients suffering from cancer and other intractable pain, the proposed investigation would be useful in preventing generalized immunosuppression while retaining the analgesic properties of opioids. It is therefore clinically important to study the mechanism of morphine-induced immunosuppression.